Viral encephalitis is a major source of morbidity and mortality both in the U.S. and throughout the world. Proven treatments for viral encephalitis are limited to only a few viruses and even when treatments exist (e.g. acyclovir for herpes simplex encephalitis) disability and death remain significant. Novel and broadly applicable strategies for the treatment of neurotropic viral infections are desperately needed. Using microarray analysis we identified death receptor signaling and peroxisome proliferator-activated receptor gamma (PPAR3) signaling as cellular signaling pathways that are significantly represented by the pattern of differential gene expression following infection of the brain with reovirus and West Nile virus (WNV), neurotropic viruses from different viral families. Preliminary data suggests that these pathways modulate virus- induced neuronal cell death and disease and provide novel therapeutic targets for viral encephalitis. In the proposed studies we will investigate the activation of these pathways following infection of the brain with reovirus, WNV and herpes simplex virus (HSV). Reovirus represents a classic in vivo experimental model of viral encephalitis. Complementary experiments using our recently developed ex vivo model of reovirus encephalitis and in vitro experiments with primary neuronal cultures provide an unmatched experimental system for the rapid evaluation of therapeutic targets for virus-induced CNS disease. To increase the impact and significance of our proposal we will perform parallel experiments with the clinically important encephalitic viruses, WNV and HSV. In order to identify novel cellular genes and pathways that can be used as therapeutic targets for viral encephalitis we will perform an inventive microarray approach using pairs of neurovirulent and neuroattenuated strains of reovirus, WNV and HSV. It is expected that genes and signaling pathways that are differentially regulated or activated following infection with neurovirulent and neuroattenuated viral strains will be directly involved in viral pathogenesis within the brain. Our experiments will thus identify a restricted set cellular genes and signaling pathways that will be evaluated as therapeutic targets for viral encephalitis. Identified genes and signaling pathways may be applicable as therapeutic targets for individual viruses. However, by identifying cellular factors that are differentially regulated following infection with multiple viruses from different families, we also expect to identify cellular targets with broad spectrum therapeutic potential for encephalitis induced by a variety of known and unknown (emerging) viruses. Our studies are also expected to increase our understanding of other human diseases characterized by the onset or disruption of neuronal death signaling.